NANOS2 suppresses the cell cycle by repressing mTORC1 activators in embryonic male germ cells

AbstractDuring murine germ cell development, male germ cells enter the mitotically arrested G0 stage, which is an initial step of sexually dimorphic differentiation. The male specific RNA-binding protein NANOS2 has a key role in suppressing the cell cycle in germ cells. However, the detailed mechanism of how NANOS2 regulates the cell cycle remains unclear. Using single-cell RNA sequencing (scRNA-seq), we extracted the cell cycle state of each germ cell in wild-type and Nanos2-KO testes, and revealed that Nanos2 expression starts in mitotic cells and induces mitotic arrest. We also found that NANOS2 and p38 MAPK work in parallel to regulate the cell cycle, suggesting that several different cascades are involved in the induction of cell cycle arrest. Furthermore, we identified Rheb, a regulator of mTORC1, and Ptma as possible targets of NANOS2. We propose that the repression of the cell cycle is a primary function of NANOS2 and that it is mediated via the suppression of mTORC1 activity by repressing Rheb in a post-transcriptional manner.

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002. REGULATION OF PLURIPOTENCY AND CELL CYCLE IN FETAL GERM CELLS

Reproduction Fertility and Development ◽

10.1071/srb09abs002 ◽

2009 ◽

Vol 21 (9) ◽

pp. 2

Author(s):

P. Western ◽

J. Van Den Bergen ◽

D. Miles ◽

R. Ralli ◽

A. Sinclair

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Transcriptional Regulation ◽

Germ Cell ◽

Germ Cells ◽

Germ Line ◽

Cell Lineage ◽

Mitotic Arrest ◽

Male Germ Cells ◽

Developmental Potential

The germ cell lineage is unique in that it must ensure that the genome retains the complete developmental potential (totipotency) that supports development in the following generation. This is achieved through a number of mechanisms that prevent the early germ cell lineage from somatic differentiation and promote the capactity for functional totipotency. Part of this process involves the retained germ line expression of key genes that regulate pluripotency in embryonic stem cells, embryonic germ cells and some embryonal carcinoma cells, the stem cells of testicular tumours. Despite this, germ cells are not intrinsically pluripotent and must differentiate along the male or female pathways, a process which requires commitment of the bi-potential primordial germ cells to the spermatogenic (male) pathway and their entry into mitotic arrest, or to the oogenic pathway (females) and entry into meiosis. This involves robust regulation of regulatory networks controlling pluripotency, cell cycle and sex specific differentiation. Our work aims to further understand the mechanisms controlling differentiation, pluripotency and cell cycle in early male and female germ cells. Our data shows that mitotic arrest of male germ cells involves strict regulation of the G1-S phase check-point through the retinoblastoma protein. In addition, suppression of pluripotency in differentiating male germ cells involves post-transcriptional regulation of OCT4, transcriptional regulation of Sox2 and Nanog and methylation of the Sox2 and Nanog promoters. Further understanding of these processes promises to lead to a greater understanding of the molecular mechanisms underlying control of pluripotency, cell cycle and differentiation in the germ line and the initiation of germ cell derived testis tumours.

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The RNA-Binding Protein DND1 Acts Sequentially as a Negative Regulator of Pluripotency and a Positive Regulator of Epigenetic Modifiers Required for Germ Cell Reprogramming

10.1101/402008 ◽

2018 ◽

Cited By ~ 1

Author(s):

Victor A. Ruthig ◽

Matthew B. Friedersdorf ◽

Jason A. Garness ◽

Steve C. Munger ◽

Corey Bunce ◽

...

Keyword(s):

Cell Cycle ◽

Germ Cells ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Embryonic Cell ◽

Negative Regulator ◽

Stem Cell Population ◽

Male Germ Cells ◽

Mitotic Proliferation

AbstractThe adult spermatogonial stem cell population arises from pluripotent primordial germ cells (PGCs) that enter the fetal testis around embryonic day 10.5 (E10.5). These cells undergo rapid mitotic proliferation, then enter a prolonged period of cell cycle arrest (G1/G0) during which they transition to pro-spermatogonia. In mice homozygous for the Ter mutation in the RNA-binding protein DND1 (DND1Ter/Ter), many germ cells fail to enter G1/G0, and give rise to teratomas, tumors in which many embryonic cell types are represented. To investigate the origin of these tumors, we sequenced the transcriptome of male germ cells in DND1Ter/Ter mutants at E12.5, E13.5, and E14.5, just prior to the formation of teratomas, and correlated this information with direct targets of DND1 identified by DO-RIP-Seq. Consistent with previous results, we found that DND1 controls the down regulation of many genes associated with pluripotency and active cell cycle, including elements of the mTor, Hippo and Bmp/Nodal signaling pathways. However, DND1 targets also include genes associated with male differentiation including a large group of chromatin regulators activated in wild type but not mutant germ cells during the transition between E13.5 and E14.5. These results suggest multiple functions of DND1, and link DND1 to the initiation of epigenetic modifications in male germ cells.

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Faculty Opinions recommendation of CREM-dependent transcription in male germ cells controlled by a kinesin.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1009563.176771 ◽

2002 ◽

Author(s):

Anthony Means

Keyword(s):

Germ Cells ◽

Male Germ Cells

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Faculty Opinions recommendation of TGFbeta signaling in male germ cells regulates gonocyte quiescence and fertility in mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.4005956.3768054 ◽

2010 ◽

Author(s):

Kate Loveland ◽

Sarah Meachem

Keyword(s):

Germ Cells ◽

Male Germ Cells ◽

Tgfbeta Signaling

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ELECTRON MICROSCOPE STUDIES ON THE DICTYOSOMES AND ACROBLASTS IN THE MALE GERM CELLS OF THE CRICKET

The Journal of Cell Biology ◽

10.1083/jcb.2.4.123 ◽

1956 ◽

Vol 2 (4) ◽

pp. 123-128 ◽

Cited By ~ 16

Author(s):

H. W. Beams ◽

T. N. Tahmisian ◽

R. L. Devine ◽

Everett Anderson

Keyword(s):

Electron Microscope ◽

Golgi Apparatus ◽

Electron Micrographs ◽

Germ Cells ◽

Light Microscope ◽

Golgi Body ◽

Duplex Structure ◽

Male Germ Cells ◽

Secondary Spermatocyte ◽

A Chain

The dictyosome (Golgi body) in the secondary spermatocyte of the cricket appears in electron micrographs as a duplex structure composed of (a) a group of parallel double-membraned lamellae and (b) a group of associated vacuoles arranged along the compact lamellae in a chain-like fashion. This arrangement of ultramicroscopic structure for the dictyosomes is strikingly comparable to that described for the Golgi apparatus of vertebrates. Accordingly, the two are considered homologous structures. Associated with the duplex structure of the dictyosomes is a differentiated region composed of small vacuoles. This is thought to represent the pro-acrosome region described in light microscope preparations. In the spermatid the dictyosomes fuse, giving rise to the acroblast. Like the dictyosomes, the acroblasts are made up of double-membraned lamellae and associated vacuoles. In addition, a differentiated acrosome region is present which, in some preparations, may display the acrosome vacuole and granule. Both the dictyosomes and acroblasts are distinct from mitochondria.

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